Irradiation of Tumor Cells Up-Regulates Fas and Enhances CTL Lytic Activity and CTL Adoptive Immunotherapy

Abstract

CD8+ CTL play important roles against malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities. Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse adenocarcinoma cell model, we examined whether exposure of these tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the tumor significantly potentiated tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of immunotherapy and radiation therapy.

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

“…23 In addition to confirming some of these findings in this study using TRAMP-C1 cells, we further found that IL-3-induced Fas antigen expression, as did RT. The effect of RT is similar to recent findings by Chakraborty et al [5][6][7] They have proposed that radiationinduced tumor phenotype changes could enhance tumor cell susceptibility to antigen-specific CTL-mediated killing. The mechanism that mediates this type of phenotypic switch by IL-3 is still unclear.…”

“…As radiation-induced changes in MHC class I, ICAM-1, and Fas expression by tumor cells irradiated in vitro also have been reported [5][6][7] we examined expression of these molecules on TRAMP-C1 cells with and without Doxregulated IL-3 expression 4 h following a single in vitro dose of 0 or 7 Gy. Radiation was given 24 h after Dox treatment.…”

“…3 The attraction of RT combined with IT is increased by findings that irradiation can modulate expression of several classes of genes in both murine and human cancers, 4 such as Fas, MHC-1, ICAM-1, and MUC-1, that might enhance their ability to serve as immune targets. 2,[5][6][7] On the other hand, while there is evidence that RT generates 'danger' signals that might mature dendritic cells (DCs) to present tumor antigen 8,9 there is no good evidence that this occurs in the clinic and such signals may be too weak to be effective. In a recent randomized phase II clinical trial study, 10 addition of recombinant vaccine administration to standard RT in patients with clinically localized prostate cancer showed that vaccination was safe and the generation of a PSAspecific cellular immune response was enhanced following RT.…”

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

“…2 One of the theoretical bases of such treatment relies on the fact that low-dose irradiation makes host immune cells sensitive to antigen priming. 3,4 Recent experiments explored the observation that irradiation-induced lymphopenia creates a huge space for lymphocyte activation and proliferation. 5 More importantly, those homeostatic proliferated cells acquire characteristics of memory and effector cells measured by phenotype and by hypersensitivity to antigen stimulation.…”

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

“…Irradiation resulted in a durable up-regulation of cell surface expression of Fas and ICAM-1 in a dose-dependent manner in murine adenocarcinoma cell lines [7]. However, in vivo it is possible that these immune-potentiating phenotypic changes would not prove beneficial if radiation were to kill all the tumor-specific infiltrating lymphocytes.…”